Epidemiological studies of individuals exposed to Sulfur Mustard (SM) have demonstrated that the acute injury caused by SM leads to severe pulmonary disorders after a single exposure, including emphysema, pulmonary fibrosis and bronchiolitis obliterans. Currently there are no medical treatments for any of these disorders. Furthermore, almost nothing is known regarding the molecular responses of cells and tissues to acute SM injury in the lung, and we could not identify any reports in the scientific literature of animal model studies of the severe pulmonary disorders that are induced by SM exposure of humans as noted above. The surprisingly high incidence of severe pulmonary complications after a single exposure to SM, even at levels that produce no acute symptom, demands that prudent measures be taken to develop therapeutic agents to either prevent or severely limit the acute injuries caused by SM and to prevent the occurrence of debilitating and life limiting pulmonary diseases. It is this combination of the severe public health impact and the lack of any effective medical intervention that would make release of SM into a crowded civilian environment a catastrophic event, which would affect many of those exposed for years and decades into the future. The urgent need for identification and testing of Top Countermeasure Therapeutics for prevention and treatment of SM injury is clearly a high priority as stated in the RFA. To accomplish this Project 3 has the following goals: 1) Establish animal models of acute SM exposure induced severe pulmonary disease (emphysema, pulmonary fibrosis, bronchiolitis obliterans) in rodents. 2) Employ these models to evaluate potential Top Countermeasure Therapeutics (TCT) that are predicted to prevent acute lung injury as therapeutic agents to prevent severe pulmonary disease. 3) Use LRRI established animal models of cigarette smoke induced emphysema and bleomycin induced pulmonary fibrosis to assess whether there is additional risk of SM exposure to individuals who are either predisposed or already have these pulmonary diseases. TCT's would also be evaluated in these animal models. 4) Determine whether skin only SM exposures induce severe pulmonary disease.